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Protein Synthesis & Folding - Enzo Life Sciences

An effective therapy must solve three major challenges in the treatment of misfolded protein diseases:

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Protein Synthesis & Folding


This induces protein misfolding diseases.
Protein misfolding can occur due to various things such as:
Environmental conditions(pH, ionic strength, temperature, and protein concentrations)
Oxidative stress
Dominant negative mutations
Error in post-translational modifications
Increase in degradation rate
Trafficking error

In other words...
protein folding is the creation of functional proteins with the help of enzymes known as chaperonins.

The project aims to understand protein misfolding and ..

Some contributors touch on the problem of the “knock-on” effect of having the cellular chaperone and proteasome machinery taken up with dealing with mutant protein, perhaps allowing other problems to slip though the net. One area that is not discussed is how the cell may deal with natively unfolded proteins. Many of these proteins have critical roles in signaling and cell cycle control, so problems with stability and turnover would have large consequences. However, most of what we currently understand about the cellular quality control mechanisms is directed at correct folding of globular proteins and the maintenance of that functional structure. Increasingly, we may learn more about how the cell regulates the stability and activity of natively unfolded proteins (NUPs). How can the usual assessments of quality control be applied to these proteins, when gain of stable folded structure cannot be used as a marker of quality?

Protein Misfolding Flashcards | Quizlet

Chiti F and Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annual Review of Biochemistry 75: 333–366.

The description of what is known about cystic fibrosis transmembrane regulator (CFTR) misfolding and degradation in cystic fibrosis is thorough, based on extensive work by a number of groups. An important and interesting section is the discussion of the correction of the folding defect as a target for CFTR therapy. The central role played by the cellular quality control mechanisms is illustrated by the methods for studying endoplasmic reticulum (ER)-associated degradation (ERAD) and ubiquitination in CFTR literature.

The editors present general concepts in the study of conformational diseases as an introduction to the field and have assembled descriptions of some of the best understood systems to illustrate the range of possible issues. These include cystic fibrosis with preventative degradation of variant proteins, and aggregation-associated problems such as Parkinson’s disease (PD) and α1-antitrypsin–associated retention of mutant protein in the endoplasmic reticulum. The General Methods section covers expression of recombinant protein, a discussion of the advantages and disadvantages of the systems available, and the use of site-directed mutagenesis and pulse-chase labeling techniques to probe the effect of disease-associated mutations on protein stability and turnover. These are techniques that have very broad application in many of the studies of conformational disease.

Protein misfolding in neurodegenerative diseases: implications ..

The three main categories of nonnative conformations—namely, stable misfolded forms, unstable misfolded forms, and aggregation-prone forms—can have three different consequences: functional deficiency, dominant-negative effects, or toxic cellular effects. The first studies of protein misfolding pathologies tended to focus most on intra- or extracellular aggregation of proteins in diseases that exhibit a gain-of-function pathology. There is increasing recognition that early species may be toxic in these processes, and there is now a shift toward investigating the cellular response to aggregation, in addition to studying the impact of the aggregation itself. Another large group of diseases involves the rapid degradation of mutant protein, resulting in a loss-of-function pathology. Increasingly, studies of different conformational diseases are highlighting the fact that the cellular responses observed with various pathologies have common features. Examination of these defective folding disorders has also highlighted the normal cellular mechanisms for dealing with protein quality control. One particular area that is increasingly well understood, and that is illuminated by studies of diseases associated with misfolding, is that of molecular chaperones and the proteolytic degradation systems such as the proteasome.

The value of this volume lies in the detailed description of particular techniques that are specific to the studies of different disease states but which, taken together, add to the growing realization that common mechanisms are involved in conformational diseases. In the case of α1antitrypsin deficiency (α1AT), the studies of the fate of α1AT and mutant α 1AT in the ER and the elucidation of the cellular response to ER retention open up a new knowledge of the course of protein transport in the ER, both under normal and stress conditions. In PD, two different routes of cellular compromise have been identified: aggregation of α-synuclein and formation of neuronal inclusions, and also loss of activity of parkin, a member of the RING-finger containing E3 ubiquitin ligase family. Loss of parkin function is associated with selective degeneration of dopaminergic neurons. This work also highlights the importance of the unfolded protein stress (UPS) response, a key feature in the study of the cellular consequences of protein misfolding. The wide scope of the book includes aberrant protein folding in cancer. Here misfolding may be due to mutations that result in inactive tumor suppressors, or alternate conformations that are regulated differently or actually lead to dominant-negative inactivation of wild-type tumor suppressors or to constitutive activation of an oncogenic protein.

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the protein synthesis machinery of the cell.

Gene therapy, as with the approaches mentionedabove, is aimed at increasing or restoring the activity of thedefective enzyme in the patient’s cells. This is not obtained bysupplying the missing enzymatic protein, but by delivering thenormal copy of the defective gene, that will direct the synthesisof the normal enzyme by the recipient’s cells.

Protein misfolding cyclic amplification - Wikipedia

Pharmacological chaperone therapy isbased on the concept that mutated misfolded proteins are recognizedby the quality control systems of the endoplasmic reticulum anddegraded. Small-molecule ligands (pharmacological chaperones) caninteract with the mutant protein, favor its correct conformation,and enhance its stability. As a result, the enzymatic activity ofthe mutant protein is partially rescued.

Future research about protein folding and misfolding:

The past decade has seen a very large increase in the description of diseases as protein misfolding or conformational disorders. Folding of the protein chain to give the functional structure, and maintenance of the functional conformation are complex and critical processes. Our understanding of the impact of alternative conformers on the cell, and how alternative conformations may compromise cellular activity or induce toxicity, is steadily growing. Biophysical methods have been relatively successful at probing the structural consequences of some disease-associated mutations; for example, three-dimensional structures of variant proteins show the impact of particular mutations, analysis of altered folding and unfolding kinetics may illustrate the affect of a mutation on protein stability in vitro, and fiber diffraction and electron microscopy studies have illuminated the structure of amyloid fibrils. This book focuses on the study of the many cellular consequences of protein misfolding. It is a guide to the techniques that have been used most successfully to highlight differences between normal and disease-related processes. It offers a tour through past successful investigations and will challenge current researchers in the field to reassess the possibilities and to apply new strategies.

Protein Misfolding, Aggregation, and Autophagy After …

An approach that has recently gained much attentionfor the treatment of diseases due to protein misfolding in generaland for LSDs specifically, is enzyme enhancement with smallmolecule pharmacological chaperones (,). Pharmacological chaperone therapyis based on the concept that loss-of-function diseases are oftendue to missense mutations that cause misfolding (abnormalconformation) of mutant proteins. The misfolded proteins arerecognized by the quality control systems of the endoplasmicreticulum and are degraded. Thus, in these so-called ‘misfoldingprotein diseases’ the loss of function is not due to the loss ofcatalytic activity, but is the result of the degradation of theaberrant protein. It has been shown that small-molecule ligands(pharmacological chaperones) can interact with the mutant protein,favor its correct conformation, and enhance its stability. As aresult, the enzymatic activity of the mutant protein is partiallyrescued (). As with ERT andother approaches directed toward replacing or increasing theresidual activity of the defective enzyme, it is reasonable tospeculate that even minor increases in activity may have afavorable impact on patient status and rate of diseaseprogression.

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